PCOS is a highly heritable (-78%) non-Mendelian disorder. Nevertheless, the common PCOS genetic susceptibility variants mapped by us and by others do not account for the observed heritability of PCOS. This so-called missing heritability has also been observed for other common, highly heritable complex traits such as T2D, height and body mass index (BMI). An explanation for this paradox that is gaining increasing experimental support is that the observed heritability is due to infrequent or rare variants with larger biological effects, in addition to the common variants already identified. Detection of these rare variants is now becoming feasible with the advent of high-throughput Next Generation DNA Sequencing methodologies. It is our overarching hypothesis that rare variants will account for a considerable proportion ofthe missing heritability of PCOS. There will be two Aims: 1) To test the hypothesis that rare genetic variants account for much of the deficit in heritability in women with PCOS. Whole genome sequencing will be performed to identify genetic variants in PCOS families with a proband and three additional affected sisters, in probands from the phenotypic extreme ofthe PCOS population and in women who remain reproductively normal despite morbid obesity. Variants that may have functional consequences that are concordant in the four affected sibs will be genotyped in the remaining family members in these families to identify those that co- segregate with PCOS. These variants, as well as novel/rare variants that are found at elevated frequency in the extreme phenotypes group(s), will be genotyped in the larger set of families with multiple affected sisters, and in the larger case-control population. 2) To test the hypothesis that rare variants identified in Aim 1 are associated with sex-specific metabolic phenotypes in PCOS. Genotype-phenotype associations will be investigated to investigate whether variants mapped with the PCOS reproductive phenotype also have a metabolic phenotype. Rare variants will be investigated in male first-degree relatives to determine if the associated metabolic phenotypes are sex-specific. RELEVANCE (See instructions): PCOS affects 7% of premenopausal women. It is a leading risk factor for type 2 diabetes in affected women and their male as well as female relatives making PCOS a major public health concern. The genetic variants we identify should provide considerable insight into the biological pathways that are disrupted in PCOS. This information should identify novel therapeutic targets and permit better disease prediction.